Monkeypox is a zoonosis, endemic to several regions within the Democratic Republic of the Congo. In humans, monkeypox virus infection can lead to a smallpox-like illness with fatal outcomes in up to 15% of patients [1-4]. The ultimate objectives of this project are to identify appropriate, effective interventions that will diminish risks for human acquisition of monkeypox virus infection, and minimize morbidity and mortality consequences of human monkeypox when it occurs. To achieve an understanding of specific risks associated with human monkeypox virus infection, in order to identify potential interventions, we will investigate both the principal mechanisms of virus transmission among humans, and the principal manner in which humans acquire infection from animals. We will further work toward the development of tools (e.g., novel point-of-care diagnostic tests), and approaches (e.g. application of a standardized surveillance case definition, [5-7]), that can promote early identification of human monkeypox and diminish inter-human spread of the virus. We propose that the field component of the research be conducted in the Tshuapa District of Equateur Province, Democratic Republic of the Congo. The population of the district is ~1.5 million persons and 600-900 cases of monkeypox are reported to the Ministry of Health annually. The six activity areas encompassed by this project are: (1) Health care worker training and community outreach. (2) Enhanced monkeypox surveillance. (3) Design and implementation of research protocols. (4) Identification of risk factors. (5) Investigation of potential animal reservoirs. (6) Evaluation of point-of-care diagnostic assays.We envision that findings from specific activities in Tshuapa district will benefit persons at risk for monkeypox virus infection throughout the country and possibly throughout the Congo Basin.